Researchers reveal how 'obesity gene' triggers weight gain

16 July 2013

Image: 3D representation of the brain, showing the areas that appeared to be affected by the FTO gene.

An international team of researchers has discovered why people
with a variation of the FTO gene that affects one in six of the
population are 70 per cent more likely to become
obese.

A new study led by scientists at King's College London, UCL
(University College London), and the Medical Research Council (MRC)
shows that people with the obesity-risk FTO variant have higher
circulating levels of the 'hunger hormone', ghrelin, in their
blood. This means they start to feel hungry again soon after eating
a meal.

Real-time brain imaging reveals that FTO gene variation also
changes the way the brain responds to ghrelin, and to images of
food, in the regions linked with the control of eating and
reward.

Together these findings explain for the first time why people
with the obesity-risk variant of the FTO gene eat more and prefer
higher calorie foods compared with those with the low-risk version,
even before they become overweight.

Dr Rachel Batterham from UCL and University College London
Hospitals, who led the research along with Dr Fernando Zelaya from
the Department of Neuroimaging at King's College London, said:
"We've known for a while that variations in the FTO gene are
strongly linked with obesity, but until now we didn't know why.
What this study shows us is that individuals with two copies of the
obesity-risk FTO variant are biologically programmed to eat more.
Not only do these people have higher ghrelin levels and therefore
feel hungrier, their brains respond differently to ghrelin and to
pictures of food - it's a double hit.

"Conventional genome-wide association studies have required much
larger numbers of subjects to reveal statistically significant
results. This study on the other hand used two carefully matched
groups of participants that differed only in their FTO profile.
Combined with neuroimaging, it has enabled us to gain a clearer
insight into how FTO interacts with ghrelin in order to modify the
way in which brain controls appetite in these two
populations.

"At a therapeutic level this arms us with some important new
insights to help in the fight against the obesity pandemic. For
example, we know that ghrelin (and therefore hunger) can be reduced
by exercise like running and cycling, or by eating a high-protein
diet. There are also some drugs in the pipeline that suppress
ghrelin, which might be particularly effective if they are targeted
to patients with the obesity-risk variant of the FTO
gene."

A quarter of all adults in the UK are now obese (have a BMI
greater than 30) and it is expected that this will rise to 60 per
cent of men, 50 per cent of women and 25 per cent of children by
2050.

Previous studies have revealed that single 'letter' variations
in the genetic code of the FTO gene are linked with an increased
risk of obesity, and this behaviour is present even in preschool
children.

Using a unique study design, scientists recruited 359 healthy
male volunteers to examine the 'real life' effects of the FTO
variation in humans. They studied two groups of participants -
those with two copies of the high obesity-risk FTO variant (AA
group) and those with the low obesity-risk (TT group). They matched
the volunteers perfectly for body weight, fat distribution and
social factors such as educational level to ensure that any
differences they saw were linked to FTO, and not to other physical
or psychological characteristics.

A group of 20 participants (10 AA and 10 TT) were asked to rate
their hunger before and after a standard meal, while blood samples
were taken to test levels of ghrelin - a hormone released by cells
in the stomach that stimulates appetite. Normally ghrelin levels
rise before meals and fall after eating, but in this study men with
the AA variation had much higher circulating ghrelin levels and
felt hungrier after the meal than the TT group. This suggests that
the obesity-risk variant (AA) group do not suppress ghrelin in a
normal way after a meal.

The scientists then used functional magnetic resonance imaging
(fMRI) in a different group of 24 participants to measure how the
brain responds to pictures of high-calorie and low-calorie food
images and non-food items, before and after a meal. Again they took
blood samples and asked the participants to rate on a scale how
appealing the images were.

Individuals with the obesity-risk FTO variant rated pictures of
high-calorie foods as more appealing after a meal than the normal
group. In addition, the fMRI study results revealed that the brains
of the two groups responded differently to food images (before and
after a meal) and to circulating levels of ghrelin. The differences
were most pronounced in the brain's reward regions (known to
respond to alcohol and recreational drugs) and in the hypothalamus
- a non-conscious part of the brain that controls
appetite.

Finally, the scientists looked at mouse and human cells to
uncover what causes increased ghrelin production at a molecular
level. They found that over-expression of the FTO gene altered the
chemical make-up of ghrelin mRNA (the template for the ghrelin
protein) and leading to higher levels of ghrelin itself. Blood
cells taken from the obesity-risk group also had higher levels of
FTO gene expression and more ghrelin mRNA than the low-risk
group.

Professor David Lomas, Chair of the MRC's Population and Systems
Medicine Board said:

"Large scale population studies have done an excellent job at
highlighting FTO as a key obesity gene. Here scientists have used
an innovative combination of human studies and more basic biology
to finally give us the 'smoking gun' linking FTO variations, hunger
and weight gain. The brain imaging adds a fascinating insight into
the role of the nervous system in obesity, which is becoming
increasingly clear. This work will undoubtedly contribute to more
targeted treatments and better outcomes for obese patients in the
future."

The research was funded by the MRC, Rosetrees Trust and the
National Institute for Health Research Biomedical Research Centres
and Wellcome Trust.

Research led by scientists at King's College London, UCL
and the Medical Research Council shows why people with a variation
of the FTO gene (known as the 'obesity gene') are 70 per cent more
likely to become obese.

The scientists found that people with the obesity-risk
FTO variant, which affects one in six of the population, have
higher levels of the 'hunger hormone' ghrelin circulating in their
blood. This means they start to feel hungry again soon after a
meal.

It's hoped that the discovery will contribute to more
targeted treatments and better outcomes for obese patients in the
future.

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